tbuckley/cabot-search huggingface dataset:
Pathological images machine learning and prediction of long-term efficacy for immunotherapy in small cell lung cancer.
Authors: Yuki Sato, Ryota Shibaki, Daichi Fujimoto, Tsukasa Nozawa, Satoshi Hara, Junji Uchida, Eisaku Miyauchi, Ryota Hiraoka, Haruko Daga, Takeshi Masuda, Satoshi Tanaka, Satoshi Ikeda, Go Saito, Hidekazu Suzuki, Shinya Sakata, Yoshihiko Sakata, Takashi Kijima, Nobuyuki Yamamoto, Yasuhiro Koh, Hiroaki Akamatsu
Journal: Journal of Clinical Oncology (2023)

8578 Background: In development of effective treatment such as immune checkpoint inhibitors (ICIs) among patients with small-cell lung cancer (SCLC), the absence of biomarkers is critical. Tumor-infiltrating lymphocytes are the main activator of antitumor immunity and could be a promising biomarker if TIL can be objectively assessed throughout the whole tumor immune microenvironment (TIME). To evaluate TIME, pathological assessment is one of the easiest ways. Recently, several studies showed that machine learning analysis can assess type of lymphocytes and their localization in pathological images. Here, we aimed to develop a novel biomarker to predict efficacy of ICI in SCLC using machine learning of pathological images. Methods: This study was a biomarker analysis of the APOLLO study which was 32-centered, prospective cohort study of patients with extensive-stage SCLC who received chemo-immunotherapy as the first-line treatment between September 2019 and September 2020. The patient who can provide sufficient tumor tissue sample from the primary tumor were enrolled. We trained a classifier which predicts 365-day progression-free survival (PFS) by all three types of pathological images (hematoxylin and eosin, programmed death-ligand 1, and CD8_FoxP3) and patient information, and developed the patient information model, pathological image model, and combination model. We used the area under the curves (AUC) to evaluate the machine learning models. Results: Of 78 patients, the median age was 78 (interquartile range, 48-87), 65 patients (83%) were male, 67 patients (86%) had a performance status of 0 or 1, and three patients (3.8%) treated with steroid therapy. Among all patients, the median PFS and the 365-day PFS rates were 145 days and 10.3%. The mean AUC of these models was 0.789 (range, 0.571-0.982) in the patient information model, 0.782 (range, 0.750-0.911) in the pathological image model, and 0.868 (range, 0.786-0.929) in the combination model, respectively. According to the median precision model, the median PFS was longer for the high efficacy group than the low efficacy group (the patient information model; hazard ratio (HR) 0.468, 95% confidence intervals (CI) 0.287-0.762. the pathological image model; HR 0.334, 95%CI 0.117-0.628. the combination model; HR 0.353, 95%CI 0.195-0.637). Conclusions: Using machine learning by pathological images, we could predict the efficacy of immunotherapy in SCLC. This study demonstrated the potential of machine learning to help the biomarker development in SCLC by assessing TIME. Clinical trial information: UMIN000038064 .
Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of gastrointestinal cancer
Authors: Ronan J Kelly, Katherine Bever, Joseph Chao, Kristen K Ciombor, Cathy Eng, Marwan Fakih, Lipika Goyal, Joleen Hubbard, Renuka Iyer, Holly T Kemberling, Smitha Krishnamurthi, Geoffrey Ku, Mindy Mintz Mordecai, Van K Morris, Andrew Scott Paulson, Valerie Peterson, Manish A Shah, Dung T Le
Journal: Journal for ImmunoTherapy of Cancer (2023)

Gastrointestinal (GI) cancers, including esophageal, gastroesophageal junction, gastric, duodenal and distal small bowel, biliary tract, pancreatic, colon, rectal, and anal cancer, comprise a heterogeneous group of malignancies that impose a significant global burden. Immunotherapy has transformed the treatment landscape for several GI cancers, offering some patients durable responses and prolonged survival. Specifically, immune checkpoint inhibitors (ICIs) directed against programmed cell death protein 1 (PD-1), either as monotherapies or in combination regimens, have gained tissue site-specific regulatory approvals for the treatment of metastatic disease and in the resectable setting. Indications for ICIs in GI cancer, however, have differing biomarker and histology requirements depending on the anatomic site of origin. Furthermore, ICIs are associated with unique toxicity profiles compared with other systemic treatments that have long been the mainstay for GI cancer, such as chemotherapy. With the goal of improving patient care by providing guidance to the oncology community, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline on immunotherapy for the treatment of GI cancer. Drawing from published data and clinical experience, the expert panel developed evidence- and consensus-based recommendations for healthcare professionals using ICIs to treat GI cancers, with topics including biomarker testing, therapy selection, and patient education and quality of life considerations, among others.
Vaccinating against cancer: getting to prime time
Authors: Ryan Chang, James L Gulley, Lawrence Fong
Journal: Journal for ImmunoTherapy of Cancer (2023)

Immunotherapies, such as immune checkpoint inhibitors, cellular therapies, and T-cell engagers, have fundamentally changed our approach to treating cancer. However, successes with cancer vaccines have been more difficult to realize. While vaccines against specific viruses have been widely adopted to prevent the development of cancer, only two vaccines can improve survival in advanced disease: sipuleucel-T and talimogene laherparepvec. These represent the two approaches that have the most traction: vaccinating against cognate antigen and priming responses using tumors in situ. Here, we review the challenges and opportunities researchers face in developing therapeutic vaccines for cancer.
Early decrease of blood myeloid-derived suppressor cells during checkpoint inhibition is a favorable biomarker in metastatic melanoma
Authors: Andrea Gaißler, Jonas Bochem, Janine Spreuer, Shannon Ottmann, Alexander Martens, Teresa Amaral, Nikolaus Benjamin Wagner, Manfred Claassen, Friedegund Meier, Patrick Terheyden, Claus Garbe, Thomas Eigentler, Benjamin Weide, Graham Pawelec, Kilian Wistuba-Hamprecht
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background The need for reliable clinical biomarkers to predict which patients with melanoma will benefit from immune checkpoint blockade (ICB) remains unmet. Several different parameters have been considered in the past, including routine differential blood counts, T cell subset distribution patterns and quantification of peripheral myeloid-derived suppressor cells (MDSC), but none has yet achieved sufficient accuracy for clinical utility. Methods Here, we investigated potential cellular biomarkers from clinical routine blood counts as well as several myeloid and T cell subsets, using flow cytometry, in two independent cohorts of a total of 141 patients with stage IV M1c melanoma before and during ICB. Results Elevated baseline frequencies of monocytic MDSCs (M-MDSC) in the blood were confirmed to predict shorter overall survival (OS) (HR 2.086, p=0.030) and progression-free survival (HR 2.425, p=0.001) in the whole patient cohort. However, we identified a subgroup of patients with highly elevated baseline M-MDSC frequencies that fell below a defined cut-off during therapy and found that these patients had a longer OS that was similar to that of patients with low baseline M-MDSC frequencies. Importantly, patients with high M-MDSC frequencies exhibited a skewed baseline distribution of certain other immune cells but these did not influence patient survival, illustrating the paramount utility of MDSC assessment. Conclusion We confirmed that in general, highly elevated frequencies of peripheral M-MDSC are associated with poorer outcomes of ICB in metastatic melanoma. However, one reason for an imperfect correlation between high baseline MDSCs and outcome for individual patients may be the subgroup of patients identified here, with rapidly decreasing M-MDSCs on therapy, in whom the negative effect of high M-MDSC frequencies was lost. These findings might contribute to developing more reliable predictors of late-stage melanoma response to ICB at the individual patient level. A multifactorial model seeking such markers yielded only MDSC behavior and serum lactate dehydrogenase as predictors of treatment outcome.
Tebentafusp in combination with durvalumab and/or tremelimumab in patients with metastatic cutaneous melanoma: a phase 1 study
Authors: Omid Hamid, Jessica C Hassel, Alexander N Shoushtari, Friedegund Meier, Todd M Bauer, April K S Salama, John M Kirkwood, Paolo A Ascierto, Paul C Lorigan, Cornelia Mauch, Marlana Orloff, Thomas R Jeffry Evans, Chris Holland, Ramakrishna Edukulla, Shaad E Abedin, Mark R Middleton
Journal: Journal for ImmunoTherapy of Cancer (2023)

Immune checkpoint inhibitors have significantly improved outcomes in first line cutaneous melanoma. However, there is a high unmet need for patients who progress on these therapies and combination therapies are being explored to improve outcomes. Tebentafusp is a first-in-class gp100×CD3 ImmTAC bispecific that demonstrated overall survival (OS) benefit (HR 0.51) in metastatic uveal melanoma despite a modest overall response rate of 9%. This phase 1b trial evaluated the safety and initial efficacy of tebentafusp in combination with durvalumab (anti-programmed death ligand 1 (PDL1)) and/or tremelimumab (anti-cytotoxic T lymphocyte-associated antigen 4) in patients with metastatic cutaneous melanoma (mCM), the majority of whom progressed on prior checkpoint inhibitors.
Incidentally Detected Giant Sellar Mass in an Infant with Delayed Milestones
Authors: Madison Woods, Vijitha S Vempuluru, Carol L Shields
Journal: Ophthalmology (2023)

A 7-month-old girl with delayed milestones was referred for suspected retinoblastoma (RB). She lacked visual fixation. Fundoscopy revealed small RBs (diameter ≤ 6 mm) in both eyes. Ultrasonography confirmed hyperechoic intraocular tumors in her right (A, arrowhead) and left (B, arrowheads) eyes. Magnetic resonance imaging revealed bilateral multifocal RBs (C, arrowheads), and a large (46 × 37 × 41 mm) intrasellar/suprasellar mass (C and D, asterisk, arrows), compressing the lateral and third ventricles (D, dotted arrows), extending into the cavernous sinus (C and D, arrows), suggestive of primitive neuroectodermal tumor associated with RB, namely trilateral RB.
Scarlett McNally: Considering the impact of human factors on teamworking and behaviour
Authors: Scarlett McNally
Journal: BMJ (2023)

The NHS needs every one of its 1.4 million staff, 1 but nobody is perfect every day of their career.Human factors have a huge impact on staff and patients.After witnessing poor behaviour in the workplace, co-workers are less effective and patients have worse outcomes. 2An unpleasant working culture also reduces camaraderie in teams and can lead to resignations.This is a vicious cycle of overwork and burnout that the NHS can't afford.
Measles, mumps, and rubella vaccine at age 6 months and hospitalisation for infection before age 12 months: randomised controlled trial
Authors: Anne Cathrine Zimakoff, Andreas Jensen, Dorthe Maria Vittrup, Emma Hoppe Herlufsen, Jesper Kiehn Sørensen, Michelle Malon, Jannet Svensson, Lone Graff Stensballe
Journal: BMJ (2023)

Abstract Objective To test for potential non-specific effects of an additional, early measles, mumps, and rubella (MMR) vaccine at age 5-7 months on risk of infection related hospitalisation before age 12 months. Design Randomised, double blinded, placebo controlled trial. Setting Denmark, a high income setting with low exposure to MMR. Participants 6540 Danish infants aged 5 to 7 months. Interventions Infants were randomly allocated 1:1 to intramuscular injection with standard titre MMR vaccine (M-M-R VaxPro) or placebo (solvent only). Main outcome measures Hospitalisations for infection, defined as all hospital contacts of infants referred from primary care for hospital evaluation and with an infection diagnosed, analysed as recurrent events, from randomisation to 12 months of age. In secondary analyses implications of censoring for date of subsequent diphtheria, tetanus, pertussis, polio, Haemophilus influenzae type B, and immunisation with pneumococci conjugate vaccine (DTaP-IPV-Hib+PCV), potential effect modification by sex, prematurity (&lt;37 weeks’ gestation), season, and age at randomisation were tested, and the secondary outcomes of hospitalisations ≥12 hours and antibiotic use were evaluated. Results 6536 infants were included in the intention-to-treat analysis. 3264 infants randomised to MMR vaccine experienced 786 hospitalisations for infection before age 12 months compared with 762 for the 3272 infants randomised to placebo. In the intention-to-treat analysis the rate of hospitalisations for infection did not differ between the MMR vaccine and placebo groups (hazard ratio 1.03, 95% confidence interval 0.91 to 1.18). For infants randomised to MMR vaccine compared with those randomised to placebo, the hazard ratio of hospitalisations for infection with a duration of at least 12 hours was 1.25 (0.88 to 1.77), and for prescriptions of antibiotics was 1.04 (0.88 to 1.23). No significant effect modifications were found by sex, prematurity, age at randomisation, or season. The estimate did not change when censoring at the date infants received DTaP-IPV-Hib+PCV after randomisation (1.02, 0.90 to 1.16). Conclusion Findings of this trial conducted in Denmark, a high income setting, do not support the hypothesis that live attenuated MMR vaccine administered early to infants aged 5-7 months decreases the rate of hospitalisations for non-targeted infection before age 12 months. Trial registration EU Clinical Trials Registry EudraCT 2016-001901-18 and ClinicalTrials.gov NCT03780179 .
Effect of CBM588 in combination with cabozantinib plus nivolumab for patients (pts) with metastatic renal cell carcinoma (mRCC): A randomized clinical trial.
Authors: Hedyeh Ebrahimi, Luis A. Meza, Keehoon Lee, Jasnoor Malhotra, Marice Alcantara, Zeynep Busra Zengin, Nazli Dizman, Ameish Govindarajan, Joann Hsu, Marian Llamas-Quitiquit, Neal Shiv Chawla, Daniela V. Castro, Benjamin D. Mercier, Sandy Liu, Alex Chehrazi-Raffle, Tanya B. Dorff, Paul Henry Frankel, Xiaochen Li, Sumanta Kumar Pal, Abhishek Tripathi
Journal: Journal of Clinical Oncology (2023)

LBA104 Background: We have previously demonstrated that the live bacterial product CBM588 may augment clinical outcomes in pts with mRCC receiving 1st-line (1L) therapy with dual immune checkpoint inhibitors (ICIs; Dizman et al Nature Medicine 2022). As tyrosine kinase inhibitors (TKIs) in combination with ICIs also represent a 1L standard of care in mRCC, we sought to determine if CBM588 would augment clinical outcome with the TKI cabozantinib (cabo) with nivo. Methods: Eligible pts were ≥18 yrs old (Karnofsky performance status ≥70%) with histologically verified (clear-cell, papillary or sarcomatoid component) mRCC and no prior systemic therapy for metastatic disease. Patients were randomized 1:2 to receive either cabo/nivo at the standard dose/schedule (40mg PO QD and 480mg IV monthly, respectively) alone or with CBM588 dosed at 80mg PO BID. The primary endpoint was the relative abundance of Bifidobacterium spp. in stool specimens at baseline and after 12 weeks of treatment. Secondary endpoints included assessment of response rate, overall survival, progression-free survival (PFS), systemic immunomodulation, and toxicity. A two-group t-test with a one-sided type I error of 0.05 was used to assess the study's primary endpoint, hypothesizing an increase in Bifidobacterium spp. with CBM588 therapy. Results: A total of 30 (20:10 M:F) pts were recruited; median age was 65 (36-84) and 5 pts (17%) had sarcomatoid features and 2 pts (7%) had predominant papillary histology. 12 (40%), 12 (40%) and 6 pts (20%) had good, intermediate and poor risk, respectively. Metagenomic sequencing of paired stool specimens showed a significant decrease in diversity from baseline to week 12 in patients receiving cabo/nivo (P=0.02); no significant difference was observed in those treated with cabo/nivo+CBM588. No significant change in Bifidobacterium spp. was observed. RR was 63% in pts receiving cabo/nivo+CBM588 vs 33% in pts receiving cabo/nivo alone. Median PFS was not reached in pts receiving CBM588 vs 5.8 mos in pts receiving cabo/nivo along (P=0.03). Grade 3/4 toxicities were observed in 44% and 42% of patients on control and experimental arms, respectively. Conclusions: In the second prospective trial assessing the addition of CBM588 to ICI-based therapy in mRCC, a consistent result with improved PFS and RR was observed. Further translational efforts are underway to characterize the mechanism through which CBM588 augments clinical activity. Clinical trial information: NCT05122546 .
First-line (1L) nivolumab (N) + ipilimumab (I) + chemotherapy (C) vs C alone in patients (pts) with metastatic NSCLC (mNSCLC) from CheckMate 9LA: 4-y clinical update and outcomes by tumor histologic subtype (THS).
Authors: David Paul Carbone, Tudor-Eliade Ciuleanu, Michael Schenker, Manuel Cobo-Dols, Stephanie Bordenave, Oscar Juan-Vidal, Juliana Janoski De Menezes, Niels Reinmuth, Eduardo Richardet, Ying Cheng, Hideaki Mizutani, Luis G. Paz-Ares, Shun Lu, Tom John, Xiaoqing Zhang, Nan Hu, David Balli, Vipul Baxi, Jaclyn Neely, Martin Reck
Journal: Journal of Clinical Oncology (2023)

LBA9023 Background: In CheckMate 9LA (NCT03215706), 1L N + I + C demonstrated durable survival benefit in pts with mNSCLC vs C alone. Here, we report updated efficacy and safety with a 4-y minimum (min) follow-up (f/u) as well as exploratory analyses of efficacy by THS, a known prognostic indicator for NSCLC. Methods: Adults with stage IV/recurrent NSCLC (no known sensitizing EGFR/ALK alterations) and ECOG PS ≤ 1 were randomized 1:1 to N 360 mg Q3W + I 1 mg/kg Q6W + 2 cycles of C (n = 361) or 4 cycles of C alone (n = 358). Pts were stratified by sex, PD-L1 (&lt; 1% vs ≥ 1%), and histology (squamous [SQ] vs non-squamous [NSQ]). Maintenance pemetrexed was allowed in the C arm (NSQ NSCLC). Assessments included OS, PFS, ORR, safety, treatment (tx)-free interval (TFI; time from last study dose to start of first subsequent systemic tx or death), and efficacy by THS (solid, acinar, or other, per modified WHO classification). Results: At a min f/u of 47.9 mo (database lock, Feb 2023; median f/u, 54.5 mo), N + I + C continued to provide long-term, durable OS benefit vs C in all randomized pts (HR, 0.74 [95% CI 0.63–0.87]; 4-y OS rates, 21% vs 16%, respectively). Similar clinical benefit was seen for N + I + C vs C across tumor PD-L1 or histology subgroups (table). In all pts treated with N + I + C (n = 358), median TFI was 2.2 mo, with 11% remaining tx-free and alive at 4y. In pts who discontinued all components of N + I + C due to tx-related adverse events (n = 61), 4-y OS rate was 41%; median TFI was 10.6 mo, with a 4-y TFI rate of 27%. In an exploratory analysis in pts with evaluable NSQ NSCLC tissue (n = 310; min f/u 36.1 mo), median OS was longer with N + I + C vs C in both solid (16.6 vs 9.3 mo) and acinar (18.7 vs 12.9 mo) THS. Updated efficacy by THS will be presented. No new safety signals were identified with longer f/u. Conclusions: With a 4-y min f/u, pts treated with N + I + C continued to derive long-term, durable efficacy benefit vs C regardless of tumor PD-L1 expression or histology, with greater magnitude of benefit in pts with tumor PD-L1 &lt; 1% or SQ histology. Exploratory analyses suggested OS benefit with N + I + C vs C in both solid and acinar subtypes. Together, these data further reinforce the use of N + I + C as an efficacious 1L tx option for pts with mNSCLC. Clinical trial information: NCT03215706 . [Table: see text]
Phase 3 THOR study: Results of erdafitinib (erda) versus chemotherapy (chemo) in patients (pts) with advanced or metastatic urothelial cancer (mUC) with select fibroblast growth factor receptor alterations (<i>FGFRalt</i>).
Authors: Yohann Loriot, Nobuaki Matsubara, Se Hoon Park, Robert A Huddart, Earle F Burgess, Nadine Houede, Severine Banek, Brigitte Laguerre, Valentina Guadalupi, Ja Hyeon Ku, Spyros Triantos, Sydney Akapame, Kris Deprince, Sutapa Mukhopadhyay, Arlene O. Siefker-Radtke
Journal: Journal of Clinical Oncology (2023)

LBA4619 Background: FGFRalt are observed in ~20% of pts with mUC. Erda is an oral selective pan-FGFR tyrosine kinase inhibitor granted accelerated approval to treat locally advanced or mUC in adults with susceptible FGFR3/2alt who have progressed after platinum-containing chemo. THOR (NCT03390504), a randomized phase 3 study, assessed whether erda provided a survival advantage vs investigator’s choice of chemo in pts with mUC who progressed after 1 or 2 prior treatments, including an anti-PD-(L)1 agent. Methods: Pts (≥18 y) with unresectable advanced/mUC and select FGFR3/2alt (mutations/fusions), ECOG performance status 0-2, adequate organ function, progression on/after prior systemic therapy (tx) that included an anti-PD-(L)1 agent, and ≤2 prior lines of tx were randomized 1:1 to receive erda (8 mg with pharmacodynamically guided uptitration to 9 mg on day 14) QD or investigator’s choice of chemo (docetaxel or vinflunine) Q3W until disease progression or intolerable toxicity. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. Results: 266 pts were randomized: 136 pts assigned to erda, 130 to chemo. In all pts, median age was 67 y; 30% had 1 prior line of tx, 70% had 2 prior lines; 74% had visceral metastases; 90% were PD-L1 low (CPS &lt;10). Median follow-up was 15.9 mo. The primary endpoint of the study was met, with erda significantly increasing OS and reducing the risk of death by 36%; median OS was 1 y (Table). These data met predefined stopping criteria for superiority. Erda also significantly improved median PFS (5.6 vs 2.7 mo) and ORR (46% vs 12%) vs chemo. No new safety signals were seen. Serious treatment-related adverse events (TRAEs) were observed in 13% and 24% of pts with erda and chemo, respectively, and grade (Gr) 3/4 TRAEs were observed in 46% and 46% of pts with erda and chemo, respectively. TRAEs leading to death were reported in 1 and 6 pts with erda and chemo, respectively. More TRAEs leading to dose reduction were observed with erda (66%) vs chemo (21%); 8% and 13% of pts had TRAEs leading to discontinuation of erda and chemo, respectively. Central serous retinopathy occurred in 23 pts (17%) with erda (Gr 1-2, 20 pts). Conclusions: In pts with FGFRalt advanced/mUC after prior treatment with PD-(L)1, erda significantly improved OS, PFS, and ORR vs investigator’s choice of chemo. Erda toxicity was consistent with the known safety profile. These results support the role of erda to treat pts with FGFRalt mUC after PD-(L)1 tx. Clinical trial information: NCT03390504 . [Table: see text]